Abstract
Metallothionein is a ubiquitous low molecular weight metalloprotein with powerful protective properties against oxygen radical-mediated cytotoxicity associated with inflammatory processes. In rheumatoid arthritis, the inflammatory damage to the synovium appears to be mediated by free radicals released by the high concentration of neutrophils found in the synovial fluid of the inflamed joint. Synovial tissue obtained during routine surgery on rheumatoid and non-rheumatoid joints was subjected to an indirect immunoperoxidase protocol for the immunolocalization of metallothionein using mouse monoclonal anti-metallothionein antibody E9, reactive against the two major isoforms of mammalian metallothionein. A layer of large dendritic-like cells situated subsynovially in the rheumatoid synovium stained very positively for the metalloprotein, both cytoplasmically and in their nuclei. These cells were not found in non-rheumatoid osteoarthritic or in undamaged synovial tissue associated with traumatic joint injury. An attempt was made to investigate their lineage using a series of antibody markers against epithelial cells, endothelial cells, smooth muscle, mesothelial cells, fibroblasts, neutrophils, dermal dendrocytes, macrophages, low and high molecular weight cytokeratin as well as a cell proliferation marker. From our results, it is suggested that these metallothionein-positive cells are probably myofibroblasts similar to the highly motile cells present in granulation tissue. They may originate from perivascular areas of synovium and their movement into the inflamed synovium may reflect the cytoprotective role of metallothionein acting as a free radical scavenger against oxidative damage
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References
Bancroft, J.D. (1967) An Introduction to Histochemical Technique, pp. 189–90. London: Butterworth.
Cerio, R., Spaull, J. & Wilson Jones, E. (1989) Histiocytoma cutis: a tumour of dermal dendrocytes (dermal dendrocytoma). Br. J. Dermatol.120, 197–206.
Cherian, M.G., Howell, S.B., Imura, N., Klaassen, C.D., Koropatnick, J., Lazo, J.S. & Waalkes, M.P. (1994) Contemporary issues in toxicology. Role of metallothionein in carcinogenesis. Toxicol. Appl. Pharmacol.126, 1–5.
Clark, R.A. (1993) Regulation of fibroplasia in cutaneous wound repair (review). Am. J. Med. Sci.306, 42–8.
Douglas-Jones, A.G., Thomas, N.D., Elmes, M.E. & Jasani, B. (1992) Immunohistochemically detectable metallothionein in granulation tissue surrounding mucosal ulceration. Histochem. J.24, 40–50.
Edwards, J.C.W. (1994) The nature and origin of synovium: experimental approaches to the study of synoviocyte differentiation. J. Anat.184, 493–501.
Eyden B.P. (1993) Brief review of the fibronexus and its significance for myofibroblastic differentiation and tumour diagnosis (review). Ultrastruct. Pathol.17, 611–22.
Gabazza, E.C., Osamu, T., Yamakami, T., Ibata, H., Sato, T., Sato, T. & Shima, T. (1994) Correlation between clotting and collagen metabolism markers in rheumatoid arthritis. Thromb. Haemostas.71, 199–202.
Halliwell, B. & Gutteridge, J.M.C. (1988a) In Free Radicals in Biology and Medicine, Chronic inflammation and the autoimmune diseases. 2nd edn, pp. 423–4. Oxford: Clarendon Press.
Halliwell, B. & Gutteridge, J.M.C. (1988b) In Free Radicals in Biology and Medicine, Chronic inflammation and the autoimmune diseases. 2nd edn, p. 429. Oxford: Clarendon Press.
Hanada, K., Baba, T., Hashimoto, I., Fukui, R. & Watanabe, S. (1992/93) Possible role of cutaneous metallothionein in protection against photo-oxidative stress — epidermal localisation and scavenging activity for superoxide and hydroxyl radicals. Photodermatol. Photoimmunol. Photomed.9, 209–13.
Jasani, B. & Elmes, M.E. (1991) Immunohistochemical detection of metallothionein. Methods Enzymol.205, 95–107.
Karin, M. (1985) Metallothioneins: proteins in search of function. Cell41, 10.
Lacour, J.P., Maquart, F.X., Bellon, G., Gillery, P., Lepeytre, P., Zeigler, G. & Ortonne, J.P. (1993) Fibroblastic rheumatism: clinical, histological, immunohistological, ultrastructural and biochemical study of a case. Br. J. Dermatol.128, 194–220.
Nakajima, K., Adachi, M., Otaki, N., Kimura, M., Tani, T., Igawa, T., Kawaharada, U. & Suzuki, K. (1991) The possible role of metallothionein in atherogenesis. In Metallothionein in Biology and Medicine (edited by C.D. Klassen & K.T. Suzuki), Chapter 29, pp. 359–73. Boca Raton, USA: CRC Press.
Roitt, I.M. (1991) Essential Immunology, 7th edn. Oxford: Blackwell Scientific Publications.
Sato, M. (1991) Metallothionein synthesis in rats exposed to radical generating agents. In Metallothionein in Biology and Medicine (edited by C.D. Klaasen & K.T. Suzuki), Chapter 17, pp. 221–35. Boca Raton, USA: CRC Press.
Schmid, K.W., Ellis, I.O., Gee, J.M.W., Darke, B.M., Lees, W.E., Kay, J., Cryer, A., Stark, J.M., Hilfmair, A., Ofner, D., Dunser, M., Margreiter, R., Daxembichler, G., Nicholson, R.I., Bier, B., Bocker, W. & Jasani, B. (1993) Presence and possible significance of immunocytochemically demonstrable metallothionein overexpression in primary ductal carcinoma of the breast. Virchows Arch.422: 153–9.
Van Dinther-Janssen, A.C.H.M., Pals, S.T., Scheper, R., Breedveld, F. & Meijer, C.J.L.M. (1990) Dendritic cells and high endothelial venules in the rheumatoid synovial membrane. J. Rheumatol.17, 11–17.
Van Dinther-Janssen, A.C.H.M., Kraal, G., Van Soesbergen, R.M., Scheper, R.J. & Meijer, C.J.L.M. (1994) Immunohistological and functional analysis of adhesion molecule expression in the rheumatoid synovial lining cell destruction. J. Rheumatol.21, 1998–2004.
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Winters, C., Jasani, B., Marchant, S. et al. Immunocytochemical identification of metallothionein- positive cells in rheumatoid synovium and analysis of their cell lineage. J Mol Hist 29, 301–307 (1997). https://doi.org/10.1023/A:1026474531060
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DOI: https://doi.org/10.1023/A:1026474531060